Abstract

Fatty esters of 2-ethylhexanoic acid (EHA) and 2-ethylhexanol (EH) are commonly used in cosmetics. Human liver and skin S9 and human plasma were used to determine the in vitro rates of clearance (CLint) of a series of compounds, with a range of 2–11 carbons on the acid or alcohol moiety and branching at the C2 position. The impact of carbon chain length on in vitro CLint was most prominent for the liver metabolism of esters of EH, while for in vitro skin metabolism it was greater for esters of EHA. The position of the branching also impacted the liver hydrolysis rates, especially for the C3, C4, and C5 esters with lower CLint in vitro rates for esters of EHA relative to those of EH. When the in vitro intrinsic clearance rates were scaled to in vivo rates of hepatic clearance, all compounds approximated the rate for hepatic blood flow, mitigating this dependence of metabolism on structure. This work shows how structural changes to the molecule can affect in vitro metabolism and, furthermore, allows for an estimation of the in vivo metabolism.

By Cindy Obringer, Cathy Lester, Michael Karb, Alex Smith, Corie A. Ellison